(N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide), (N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide) and N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethanesulfonamide are possible intermediates in the synthesis of Rosuvastatin and its pharmaceutically acceptable salts. Rosuvastatin calcium, chemically described as bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt, is a synthetic lipid-lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoA Reductase inhibitor). HMG-CoA reductase inhibitors are commonly referred to as “statins.” Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Therefore, Rosuvastatin calcium is used in the treatment of hypercholesterolemia and mixed dyslipidemia.
The EP 521471 A1 discloses Rosuvastatin and a process for its preparation, among others by a process comprising a step of preparing N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide by reduction of a suitable ester derivative thereof with diisobutylaluminium hydride (DIBAL-H) as a reduction reagent. Furthermore, WO2008/059519 A2 also describes the preparation of Rosuvastatin via N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide as intermediate obtained by reduction of a suitable ester thereof by means of DIBAL-H.
International patent application WO2007/017117 A1 describes the preparation of Rosuvastatin via N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide as the intermediate. This intermediate is prepared by nucleophilic substitution of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide by means of HBr as the source of nucleophile.
The object of the present invention is to provide an improved process for preparing N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide, N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide and N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethanesulfonamide, so as to provide valuable intermediates for the preparation of Rosuvastatin and pharmaceutically acceptable salts thereof.